1. Field of the Invention
The present invention relates to a dried and stabilized composition of a prostaglandin E group compound (hereinafter, it is referred to as PGE group compound) and to the process for the preparation thereof. More particularly, the invention relates to a dried and stabilized PGE group composition prepared from a PGE group compound with calcium lactate and/or amylopectin.
The composition of the present invention is particularly advantageous for pharmaceutical preparations.
Further, the invention relates to a stabilized pharmaceutical preparation prepared from the abovementioned dried and stabilized PGE group composition and to the process for the preparation thereof.
PGE group compounds are shown by the following basic structural formula ##STR1##
The compounds having the above described basic structure are characterized by the oxo group at position 9 and the hydroxy group at position 11, and include PGE.sub.1, PGE.sub.2, PGE.sub.3, etc. which are named according to the number and position of the double bond in the molecule. PGE group compounds in this invention include the compounds having substituent(s) such as the methyl group, methoxy group, hydroxy group, oxo group, etc. at various position(s) of the structure. Suitable examples are 16-methyl-PGE.sub.2, 3-methyl-PGE.sub.2, 3,6(R)-dimethyl-PGE.sub.2, 17-oxo-15-epi-PGE.sub.2, 16(R)-hydroxy-PGE.sub.2, 15(R)-methyl-PGE.sub.2 methyl ester, 15(S)-methyl-PGE.sub.2 methyl ester, 16,16-dimethyl-PGE.sub.2 methyl ester, 4(R),16(R)-dimethyl-PGE.sub.2, 4(R),16(S)-dimethyl-PGE.sub.2, 4(S),16(R)-dimethyl-PGE.sub.2, 4(S),16(S)-dimethyl-PGE.sub.2, 16(R,S)-methyl-20-methoxy-PGE.sub.2, 16(S)-methyl-20-methoxy-PGE.sub.2.
2. Description of the Prior Art
The PGE group compounds exhibit, even at a small dose, various physiological effects such as control of the contractive force of uterus, hypotensive activity, treatment and prophylaxis of digestive organ ulcers, control of lipid metabolism, bronchodilator activity, etc.
However, the application of PGE group compounds in a number of areas has been severely hampered by their instability, especially in solution. (see Brummer; J. Pharm. Pharmacol., 23, 804-805 (1971) and Karmin et al; European J. Pharmacol., 4, 416-420 (1968))
For the preparation of a stable composition of PGE.sub.2, several methods are heretofore known; U.S. Pat. No. 3,749,800 describes a concentrated stock solution of PGE.sub.2 in an anhydrous, water miscible, pharmacologically-acceptable alcohol; Belgian Pat. No. 790,840 describes a solution in an anhydrous organic aprotic dipolar solvent such as N,N-dimethylacetamide. These methods are applied for the concentrated preparation of injections and this preparation is diluted on the occasion of administration. In U.S. Pat. No. 3,851,052, there is disclosed a stabilized PGE group composition with an alkali metal sulfite salt, however, the stabilization effect by the method is limited to a stock solution of a PGE group compound in alcohol together with an alkali metal sulfite salt and the potency of the solution becomes only about 70% when the solution is stored for 13 days at 60.degree. C.
U.S. Pat. No. 3,826,823 discloses a solid dispersion of prostaglandin in polyvinyl pyrrolidone (PVP). In this process highly hygroscopic PVP is apt to absorb moisture in the air and consequently, the solid dispersion is difficult to pulverize and tends to be sticky by the absorption of moisture in the air. Moreover, PVP is reported to cause hepatotoxicity and can not be suitable for pharmaceutical preparations.
U.S. Pat. No. 3,903,297 discloses substituted prostaglandin derivatives and their formulations; however the stability of the formulations are not mentioned.
U.S. Pat. No. 3,917,864 refers to the lyophilized composition of prostaglandin F.sub.1.alpha. together with mannitol.
In German Offenlegungsschrift No. 2,451,161, some of the present inventors had invented a stabilized prostaglandin composition with the addition of thiol compounds, dextrin, dextran, lower alkyl cellulose or salt of deoxycholic acid.